The invention is illustrated in the following with reference to the production of a synthetic vaccine against influenza. It ought to be understood that the invention is not restricted to this specific embodiment, and that the principles of preparation of synthetic antigenic fragments can be applied to other viruses, and that such products can be the basis for the production of vaccines against other diseases.
Influenza virus appears as three subtypes, A, B and C, of which subtype A comprises the major antigenic variants that are associated with pandemics. This subtype is capable of changing its antigenic identity so remarkably that the specific immunity established in response to infection or vaccination by a particular strain may give little or no protection against viruses which subsequently arise. Because of these variants influenza continues to be a major epidemic disease in man.
Presently existing vaccines against influenza consist of either live, attenuated virus, or killed virus vaccines. The live vaccines are more potent than the killed ones, but are not considered safe enough, and the duration of the protection provided by either vaccine is rather short.
The two principal antigenic components of the virus are: (1) The neuraminidase which is common to many influenza strains and antibodies against it are almost non-neutralizing and non-protective, and (2) the hemagglutinin (HA), which undergoes gradual changes (drifts), which is a strong immunogen and is responsible for the serological specifity of the different viral strains. Antibodies against the HA render the immune host less susceptible to infection with a virus containing the same hemagglutinin. Complexes of the hemagglutinin and the neuraminidase have also been utilized as potential vaccines, but these "subunit vaccines" proved to be poorly immunogenic in unprimed animals and in man.
The HA is a molecule of 75,000 to 80,000 dalton, and a CNBr cleavage fragment of it was found to be responsible for the immunological activity of the intact protein and it was found to be able to elicit antibodies which inhibit its hemagglutinin activity. A non-identified 16-amino acid residue tryptic peptide of the hemagglutinin was also reported as possessing antigenic specificity. Neither of these fragments nor any other similar natural or synthetic material has been used for eliciting an in vivo protective effect.
In other systems short synthetic peptides corresponding to fragments of particular proteins have been shown to carry antigenic properties of the intact protein. Thus, synthetic antigens have been used for provoking antibodies against lysozyme or carcinoembryonic antigen (CEA). The same approach was employed for eliciting anti-viral response: A synthetic 20-amino acid residue peptide corresponding to a fragment of the coat protein of the MS-2 coliphage has been synthesized and attached to a synthetic carrier. This conjugate, when injected in complete Freund's adjuvant, elicited in rabbits and guinea pigs antibodies capable of neutralizing the viability of the phage.